rs1131620

Variant names:

• chr19-40611963-A-G
• rs1131620
• NM_001042545.2:c.2158A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-40611963-A-G
• chr19-40611963-A-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001042545.2(LTBP4):​c.2158A>G​(p.Thr720Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 1,610,558 control chromosomes in the GnomAD database, including 151,466 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. T720T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.47 (17543 hom., cov: 32)
  • Exomes 𝑓: 0.42 (133923 hom.)
• Consequence: LTBP4 NM_001042545.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.01
• Publications: 58 publications found

Genes affected

LTBP4 (HGNC:6717): (latent transforming growth factor beta binding protein 4) The protein encoded by this gene binds transforming growth factor beta (TGFB) as it is secreted and targeted to the extracellular matrix. TGFB is biologically latent after secretion and insertion into the extracellular matrix, and sheds TGFB and other proteins upon activation. Defects in this gene may be a cause of cutis laxa and severe pulmonary, gastrointestinal, and urinary abnormalities. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]

LTBP4 Gene-Disease associations (from GenCC):

• cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.6001874E-5).
• BP6: Variant 19-40611963-A-G is Benign according to our data. Variant chr19-40611963-A-G is described in ClinVar as Benign. ClinVar VariationId is 163946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042545.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP4	NM_001042545.2	MANE Select	c.2158A>G	p.Thr720Ala	missense	Exon 14 of 30	NP_001036010.1	Q8N2S1-2
	LTBP4	NM_001042544.1		c.2359A>G	p.Thr787Ala	missense	Exon 17 of 33	NP_001036009.1	Q8N2S1-1
	LTBP4	NM_003573.2		c.2248A>G	p.Thr750Ala	missense	Exon 17 of 33	NP_003564.2	B3KXY6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP4	ENST00000396819.8	TSL:1 MANE Select	c.2158A>G	p.Thr720Ala	missense	Exon 14 of 30	ENSP00000380031.5	Q8N2S1-2
	LTBP4	ENST00000308370.11	TSL:1	c.2359A>G	p.Thr787Ala	missense	Exon 17 of 33	ENSP00000311905.8	Q8N2S1-1
	LTBP4	ENST00000204005.13	TSL:1	c.2248A>G	p.Thr750Ala	missense	Exon 17 of 33	ENSP00000204005.10	A0A0C4DH07

Frequencies

GnomAD3 genomes AF: 0.472 AC: 71654 AN: 151746 Hom.: 17534 Cov.: 32

Gnomad AFR AF: 0.579

Gnomad AMI AF: 0.358

Gnomad AMR AF: 0.380

Gnomad ASJ AF: 0.556

Gnomad EAS AF: 0.400

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.528

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.417

Gnomad OTH AF: 0.452

GnomAD2 exomes AF: 0.439 AC: 107038 AN: 243614 AF XY: 0.448

Gnomad AFR exome AF: 0.576

Gnomad AMR exome AF: 0.301

Gnomad ASJ exome AF: 0.546

Gnomad EAS exome AF: 0.413

Gnomad FIN exome AF: 0.510

Gnomad NFE exome AF: 0.414

Gnomad OTH exome AF: 0.433

GnomAD4 exome AF: 0.424 AC: 618403 AN: 1458692 Hom.: 133923 Cov.: 61 AF XY: 0.430 AC XY: 311831 AN XY: 725188

African (AFR) AF: 0.592 AC: 19784 AN: 33436

American (AMR) AF: 0.311 AC: 13780 AN: 44344

Ashkenazi Jewish (ASJ) AF: 0.543 AC: 14125 AN: 26018

East Asian (EAS) AF: 0.366 AC: 14491 AN: 39606

South Asian (SAS) AF: 0.558 AC: 47790 AN: 85662

European-Finnish (FIN) AF: 0.511 AC: 27184 AN: 53198

Middle Eastern (MID) AF: 0.499 AC: 2873 AN: 5760

European-Non Finnish (NFE) AF: 0.406 AC: 450998 AN: 1110396

Other (OTH) AF: 0.454 AC: 27378 AN: 60272

GnomAD4 genome AF: 0.472 AC: 71707 AN: 151866 Hom.: 17543 Cov.: 32 AF XY: 0.477 AC XY: 35393 AN XY: 74236

African (AFR) AF: 0.579 AC: 23980 AN: 41414

American (AMR) AF: 0.379 AC: 5790 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.556 AC: 1926 AN: 3466

East Asian (EAS) AF: 0.399 AC: 2057 AN: 5150

South Asian (SAS) AF: 0.553 AC: 2657 AN: 4804

European-Finnish (FIN) AF: 0.528 AC: 5582 AN: 10566

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.417 AC: 28295 AN: 67898

Other (OTH) AF: 0.452 AC: 950 AN: 2102

Alfa AF: 0.431 Hom.: 48892

Bravo AF: 0.463

TwinsUK AF: 0.400 AC: 1484

ALSPAC AF: 0.401 AC: 1545

ESP6500AA AF: 0.563 AC: 2374

ESP6500EA AF: 0.422 AC: 3549

ExAC AF: 0.442 AC: 53474

Asia WGS AF: 0.484 AC: 1682 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies (4)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.035
DANN	Benign	0.63
DEOGEN2	Benign	0.039	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.0053	T
MetaRNN	Benign	0.000016	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.46	N
PhyloP100		-2.0
PrimateAI	Benign	0.29	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.15
Sift	Benign	0.90	T
Sift4G	Benign	0.85	T
Polyphen		0.0	B
Vest4		0.019
MPC		0.33
ClinPred		0.0026	T
GERP RS		2.5
PromoterAI		-0.013	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.038
gMVP		0.20
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1131620; hg19: chr19-41117869; COSMIC: COSV52582827; COSMIC: COSV52582827;